Amino acid derivatives and methods of making the same

ABSTRACT

Disclosed are novel compounds represented by Structural Formula II, IX or XXVIII:  
                 
 
     R 1 , R 21  and R 22  are independently an aliphatic group, a substituted aliphatic group, an aromatic group or a substituted aromatic group.  
     R 2  is —NR 4 R 5  or —N + ≡C − .  
     Alternatively, R 1  and R 2 , taken together with the methine group to which they are bonded, are a moiety represented by the following structural formula:  
                 
 
     R 3  is —NH 2 , —OH, —OC(O)H or —OR 9 .  
     R 5 , R 6  and R 7  are independently —H or an amine protecting group.  
     R 8  is —H, —OH or —OR 8 .  
     R 9  is an alcohol protecting group.  
     Also disclosed are methods of preparing these compounds.

RELATED APPLICATIONS

[0001] This application is a divisional of U.S. application Ser. No.10/178,180, filed Jun. 21, 2002, which is a divisional of U.S.application Ser. No. 09/342,855, filed Jun. 29, 1999, now U.S. Pat. No.6,479,669, which is a continuation-in-part of U.S. application Ser. No.09/074,765, filed May 8, 1998, now abandon, which claims the benefit ofU.S. Provisional Application No. 60/046,129, filed May 9, 1997. Theentire teachings of the above applications are incorporated herein byreference.

BACKGROUND OF THE INVENTION

[0002] A peptide mimetic is a compound which has sufficient structuralsimilarity to a peptide so that the desirable properties of the peptideare retained by the mimetic. For example, peptide mimetics are alreadybeing used as protease inhibitors for treating HIV infection, asdisclosed in Tung, et al., WO 94/05639, Vazquez, et al., WO 94/04491,Vazquez, et al., WO 94/10134 and Vaquez, et al., WO 94/04493. The entirerelevant teachings of these publications are incorporated herein byreference. To be useful as a drug, a peptide mimetic should retain thebiological activity of a peptide, but also have one or more propertieswhich are improved compared with the peptide which is being mimicked.For example, some peptide mimetics are resistant to hydrolysis or todegradation in vivo. One strategy for preparing a peptide mimetic is toreplace one or more amino acid residues in a peptide with a group whichis structurally related to the amino acid residue(s) being replaced andwhich can form peptide bonds. The development of new amino acidderivatives which can be used to replace amino acid residues in peptideswill advance the development of new peptide mimetic drugs.

[0003] Combinatorial libraries have great utility for identifying leadsin drug discovery. The “Ugi” reaction, shown schematically below, iscommonly used to generate combinatorial libraries.

[0004] The ability to identify new, structurally diverse compounds whichcan participated in the Ugi reaction are needed to identify new drugleads from combinatorial libraries which are constructed using the thisreaction.

SUMMARY OF THE INVENTION

[0005] The present invention includes novel isonitriles, diisonitriles,triamines, oxazolidines, oxazolines and imidazoles, and methods ofpreparing these novel compounds.

[0006] One embodiment of the present invention is a compound representedby Structural Formula I:

[0007] or salts thereof.

[0008] In Structural Formula I, R₁ is an aliphatic group, a substitutedaliphatic group, an aromatic group or a substituted aromatic group.Preferably, R₁ is an amino acid side-chain or a protected amino acidside-chain.

[0009] R₂ is —NR₅R₆ or —N⁺≡C⁻.

[0010] Alternatively, R₁ and R₂, taken together with the methine groupto which they are bonded, are a moiety represented by the followingstructural formula:

[0011] R₃ is —NH₂, —OH, —OC(O)H or —OR₉.

[0012] R₄ is —N⁺≡C⁻, —NH₂, or —NO₂.

[0013] R₅, R₆ and R₇, are each, independently, —H or an amine protectinggroup.

[0014] R₈ is —H, —OH or —OR₉.

[0015] R₉ is an alcohol protecting group.

[0016] One embodiment of the present invention is an isonitrilerepresented by Structural Formula II:

[0017] Isonitriles represented by Structural Formula II are prepared bydehydrating a N-alkyl formamide represented by Structural Formula III:

[0018] The N-alkyl formamide of Structural Formula III is prepared byformylating a starting material represented by Structural Formula IV:

[0019] In Structural Formulas II, III and IV, R₁, R₂, and R₃ are definedas in Structural Formula I. In a preferred embodiment, R₁ is benzyl,sec-butyl, the side-chain of tryptophan, —(CH₂)₄—NH(t-butoxycarbonyl),—CH₂COO(t-butyl), —CH(O-benzyl)-CH₃, or —(CH₂)₂—S—CH₃; and R₃ is—OCH(O).

[0020] Another embodiment of the present invention is a 2-hydroxypropylisonitrile represented by Structural Formula V:

[0021] Isonitriles represented by Structural Formula V are prepared byreacting a trialkylsilyl cyanide and ZnI₂ with a starting compoundrepresented by Structural Formula VI:

[0022] In Structural Formulas V and VI, R₁ and R₂ are as described formStructural Formula I.

[0023] Another embodiment of the present invention is a2-amino-1-nitropropane represented by Structural Formula VII:

[0024] The 2-amino-1-nitropropanes represented by Structural Formula VIIare prepared by reducing an oxime ether of a compound represented byStructural Formula VIII:

[0025] In Structural Formulas VII and VIII, R₁ and R₂ are as describedfor Structural Formula I. R₁₈ is an aliphatic group, a substitutedaliphatic group, an aromatic group or a substituted aromatic group.Preferably R₁₈ is a C1-C3 alkyl group.

[0026] Another embodiment of the present invention is an imidazolerepresented by Structural Formula IX:

[0027] Imidazoles represented by Structural Formula IX are prepared byreacting an aliphatic carboxylic acid and an ammonium salt of thealiphatic carboxylic acid with a compound represented by StructuralFormula X:

[0028] In Structural Formulas IX and X, R₂₁ and R₂₂ are each,independently, —H, an aliphatic group, a substituted aliphatic group, anaromatic group or a substituted aromatic group. R₂₁ is preferably aC1-C4 straight chain or branched alkyl group. R₂₂ is preferably analiphatic side-chain of a naturally occurring amino acid.

[0029] Another embodiment of the present invention is an oxazolidinerepresented by Structural Formula XI:

[0030] R₄₁ is an aliphatic group, a substituted aliphatic group, an arylgroup or a substituted aryl group. R₄₁ is preferably the side-chain of anaturally occurring amino acid or a protected side-chain of a naturallyoccurring amino acid.

[0031] R₄₂ is —NR₅R₆.

[0032] Alternatively, R₄₁ and R₄₂, taken together with the methine groupto which they are bonded, form a moiety represented by StructuralFormula XII:

[0033] R₄₃ is an aliphatic group, a substituted aliphatic group, an arylgroup or a substituted aryl group. R₄₃ is preferably a C1-C3 alkyl groupor substituted alkyl group.

[0034] In Structural Formulas XI and XII, R₅, R₆, R₇ and R₈ are asdescribed for Structural Formula I. In a preferred embodiment, one of R₅and R₆ is —H.

[0035] The compounds represented by Structural Formula XI are preparedby reacting a 2-hydroxy-1-propylamine represented by Structural FormulaXIII and a compound represented by Structural Formula XIV:

 R₄₃—X  XIV.

[0036] R₄₁₋₄₃ are as described for Structural Formula XI.

[0037] X is —CHO, —COOR or —C(═NH)OR. R is an aliphatic group, asubstituted aliphatic group, an aryl group or a substituted aryl group.R is preferably a C1-C4 alkyl group.

[0038] The compounds of the present invention can be used as reagents inthe Ugi reaction or to prepare peptide mimetics, and, consequently, canbe used to identify new drug leads. The compounds of the presentinvention can be obtained in optically pure form from the disclosedmethods, if the starting materials are optically pure. Using opticallypure reagents in combinatorial reactions such as the Ugi reaction shouldresult in conformationally restricted adducts which can be utilized tomap the three-dimensional structure of receptor sites.

DETAILED DESCRIPTION OF THE INVENTION

[0039] The features and other details of the method of the inventionwill now be more particularly described and pointed out in the claims.It will be understood that the particular embodiments of the inventionare shown by way of illustration and not as limitations of theinvention. The principle features of this invention can be employed invarious embodiments without departing from the scope of the invention.All parts and percentages are by weight unless otherwise specified.

[0040] Compounds represented by Structural Formulas I are derived fromamino acid precursors. The amino alcohols can be prepared by a methodsummarized in Scheme I and described in detail in U.S. Pat. No.5,475,138, the entire teachings of which are incorporated herein byreference. In Scheme I, R₁, R₅ and R₆ are as described above. Thestarting material in Scheme I, compound XV, is an amino acid wherein theamine functionality is protected. The compounds of the present inventionrepresented by Structural Formula I are derived from compound XVIII ofScheme I.

[0041] In a preferred embodiment of the present invention, R₅ and R₆ ofStructural Formula XVIII are each —H and the alcohol group is protected.This compound is represented by Structural Formula XIX:

[0042] Methods for protecting alcohols are known to those skilled in theart and can be found in Greene and Wuts, “Protective Groups in OrganicSynthesis, 2^(nd),” John Wiley & Sons (1991). A diamino compoundrepresented by Structural Formula XIX can be formylated to form acompound represented by Structural Formula XX:

[0043] Compound XX can be dehydrated to form the diisonitrilerepresented by Structural Formula XXI:

[0044] In another preferred embodiment, the alcohol group of compoundXVIII can be protected and the unprotected amine can be formylated toform a N-alkyl formamide represented by Structural Formula XXII:

[0045] The N-alkyl formamide represented by Structural Formula XXII canbe dehydrated to form an isonitrile represented by Structural FormulaXXIII:

[0046] When the amino acid proline or a substituted proline is used as astarting material in Scheme I, the diaminoalcohol synthesized can berepresented by Structural Formula XXIV:

[0047] Compound XXIV can be formylated to form a compound represented byStructural Formula XXV:

[0048] A compound represented by Structural Formula XXV can bedehydrated to form an isonitrile represented by Structural Formula XXVI:

[0049] Procedures for carrying out the dehydration reaction to form anisonitrile, for example, compounds represented by Structural FormulasII, XXI, XXIII or XXVI from an N-alkyl formamide, for example, compoundsrepresented by Structural Formulas III, XX, XXII or XXV, respectively,are disclosed in “Organic Functional Group Preparations” S. R. Sandlerand W. Karo, Volume III, 2^(nd) edition, Academic Press, Inc. San Diego,1989, pages 206-235. The entire teachings of pages 206-235 in “OrganicFunctional Group Preparations” are incorporated herein by reference.Isonitriles are prepared by elimination of water from N-alkylformamides. The elimination reaction is accomplished by treatment of theN-alkyl formamide with phosgene and a tertiary amine (see for reviewHoffmann, et al., Isonitrile Chemistry, (1971), Academic Press, NewYork, p. 10-17; Ugi, et al., Angew. Chem. Int. Ed. Engl., (1965),4:472). Other reagents can also be used, for example, tosyl chloride inquinoline; phosporous oxychloride (POCl₃) and a tertiary amine;(chloromethylene) dimethylammonium chloride ((CH₃)₂N═CHCl⁺Cl⁻) (seeWalborsky, et al., J. Org. Chem., (1972), 37:187); diphosgene(ClC(O)C(O)Cl) (see Skorna and Ugi, Angew. Chem. Int. Ed. Engl. (1977);16:259), 2-chloro-3-ethylbenzoxazolium tetrafluoroborate (see Echigo, etal., Chem. Lett., (1977), 697); or a complex oftriphenylphosphine-carbon tetrahalide-triethylamine (see Bestmann, etal., Liebigs Ann. Chem. (1968), 718:24).

[0050] As used herein “formylation” of an amine is addition of a formylgroup (i.e., —C(O)H) to the amine. Procedures for formylating the aminocompounds represented by Structural Formulas IV, XVIII, XIX and XXIV toprepare N-alkyl formamides represented by Structural Formulas III, XX,XXII and XXV, respectively, are described in Greene and Wuts,“Protective Groups in Organic Synthesis,” John Wiley & Sons (1991),pages 349-350. For example, a primary or secondary amine can beformylated in about 78-90% yield by treating the amine with a solutionof 98% formic acid and 2% acetic anhydride at 25° C. for 1 h (seeSheehan and Yang, J. Am. Chem. Soc., (1958), 80:1154 and Jahngen, etal., Synth. Commun. (1982), 12:601). Primary or secondary amines canalso be formylated in about 87-90% yield by treatment with formic acidand DCC in pyridine at 0° C. for 4 h (see Waki and Meienhofer, J. Org.Chem., (1977), 42:2019). Another method of formylating a primary orsecondary amine is by treatment with t-butyldimethylsilyl chloride,4-dimethylaminopyridine and triethyl amine in dimethyl formamide at35-60° C. This method yields the formylated amine in about 65-85% yield(Djuric, J. Org. Chem., (1984), 49:1311). Other methods are described inGreene and Wuts, “Protective Groups in Organic Synthesis.”

[0051] Isonitriles represented by Structural Formula V can also beprepared by reacting trimethylsilylcyanide (TMS-CN) and a catalyticamount of ZnI₂ with an epoxide represented by Structural Formula VI. Thereaction is typically carried out in a polar aprotic solvent such asmethylene chloride, chloroform or dichloroethane, preferably methylenechloride. The solvent is preferably dried before use. An excess ofTMS-CN relative to the epoxide can be used, for example, from one toabout ten equivalents of TMS-CN relative to epoxide, preferably from oneto about two equivalents. The reaction is carried out at concentrationsof from about 0.01 M to about 5.0 M, preferably 0.1 M to about 1.0 M,and at temperatures ranging from about 0° C. to about 80° C., preferablyat the reflux temperature of methylene chloride.

[0052] Epoxides represented by Structural Formula VI can be prepared bymethods disclosed in Vazquez, et al., WO 94/04491, the entire relevantteachings of which are incorporated herein by reference.

[0053] A 2-amino-3-nitropropane represented by Structural Formula VIIcan be prepared from, for example, an oxime ether represented byStructural Formula VIII using hydride reducing agents such as sodiumborohydride, lithium borohydride, lithium aluminum hydride, lithiumtriethyl borohydride and the like, or by using a borane reducing agentsuch as diborane. The reaction is generally carried out in an etherealsolvent such as tetrahydrofuran, diethyl ether, glyme, diglyme ordioxane using from one to about twenty reducing equivalents, preferablyfrom about one to about three reducing equivalents. Typically, reactiontemperatures range from about −20° C. to about 50° C., and arepreferably from about −5° C. to ambient temperature. The concentrationof the reagents range from about 0.01 M to about 2.0 molar, preferablyabout 0.1 M to about 1.0 M. Specific conditions for carrying out thisreaction are disclosed in WO 96/39399 by Sun, et al., the entireteachings of which are incorporated herein by reference.

[0054] The syn or anti geometric isomer of an oxime ether can bestereoselectively reduced to preferentially form one stercoisomer byperforming the reduction in the presence of a suitable chiral auxiliaryagent. “Chiral auxiliary agent” is a compound which, when added to areaction mixture, results in a reaction having a higher degree ofstereoselectivity than in the absence of the compound. For example, inthe conversion of the oxime ether represented by Structural Formula VIIIto the compound represented by Structural Formula VII, a largerenantiomeric excess of the 2S stereoisomer (or 2R stereoisomer) isformed in the presence of the chiral auxiliary agent than in itsabsence. Examples of suitable chiral auxiliary agents include chiralamines such as (−)-norephedrine, (+)-norephedrine, (−)-ephedrine,(+)-ephedrine and (+)-2-amino-1-(2-methylphenyl)-1-propanol and(−)-2-amino-1-(2-methylphenyl)-1-propanol. One geometric isomer of anoxime ether (e.g., syn) together with one enantiomer of a chiralauxiliary agent (e.g., (+)-ephedrine) will preferentially form onestereoisomer product (e.g., 2S). Using either the opposite oxime ethergeometric isomer or the opposite chiral auxiliary enantiomer willpreferentially form the opposite stereoisomer product (e.g., 2R). Usingthe opposite geometric isomer oxime ether and the opposite chiralauxiliary enantiomer will preferentially form the same stereoisomerproduct (e.g., 2S). Other suitable chiral auxiliary agents, as well asspecific conditions for stereoselectively reducing an oxime ether, aredisclosed in U.S. Pat. No. 5,200,561 to Konya, et al., Itsuno, et al.,J. Chem. Soc. Perkin Trans. I, 1985:2039 and Sakito, et al., Tetrahedron29:223 (1988), the entire teachings of which are incorporated herein byreference. Typically, between about 0.5 and about 1.0 moles of chiralauxiliary agent per mole of reducing agent are used.

[0055] Oxime ethers represented by Structural Formula VIII, which areused to form 2-amino-1-nitropropanes represented by Structural FormulaVII can be prepared by reacting approximately equimolar amounts anitroketone represented by Structural Formula XVI with the hydrochloridesalt of NH₂OR₁₈ in pyridine.

[0056] R₁, R₅, and R₆ are as described for Structural Formula I, and R₁₈is as described for Structural Formula VIII. Specific conditions forperforming this reaction are described, for example, in Sun, et al., WO96/39399. The syn and anti isomers can be separated by columnchromatography. The prepartion of nitroketone starting materials aredescribed in U.S. Pat. No. 5,475,138, the entire teachings of which areincorporated herein by reference.

[0057] The 2-amino-1-nitropropane represented by Structural Formula VIIcan be further reacted with a nitro group reducing agent to form adiamino compound represented by Structural Formula XXVII.

[0058] Reagents suitable for reducing a nitro group to an amine are wellknown in the art and include hydrogenation catalysts such as PtO₂ andPd. The nitro compound is dissolved in an alcoholic or ethereal solventunder a hydrogen atmosphere (from about one to about 100 pounds persquare inch) in the presence of the hydrogenation catalyst. Other nitroreducing agents include hydride reducing agents such as lithium aluminumhydride, lithium triethyl borohydride and lithium aluminum trimethoxyhydride. The procedure used to perform this reduction is similar tothose described above for the reduction of the oxime ether, modified toinclude a suitable nitro reducing agents. Specific procedures aredescribed in U.S. Pat. No. 5,475,138 and in Brown, et al., AldrichimicaActa, 12:3 (1979) and references cited therein, the entire relevantteachings of which are incorporated herein by reference.

[0059] The compound represented by Structural Formula IX can be preparedby reacting an aliphatic carboxylic acid and an ammonium salt of thealiphatic carboxylic acid with a compound represented by StructuralFormula X. Specific procedures for carrying out this reaction areprovided in von Geldern, et al., J. Med. Chem., 39:957 (1996), theentire teachings of which are hereby incorporated by reference.

[0060] The nitro group in the compounds represented by StructuralFormula IX can be hydrogenated to form a product with an amine group.Suitable hydrogenation conditions are described hereinbelow. This amineproduct can be used as a reagent in the Ugi reaction to prepare newcombinatorial libraries for drug discovery.

[0061] The compound represented by Structural Formula XI can be preparedby mixing an amino alcohol represented by Structural Formula XIII and acompound represented by Structural Formula XIV in a solvent such asacetonitrile, methylene chloride, chloroform or methanol (preferably ananhydrous solvent) and allowing the compounds to react. An excess ofeither reagent can be used. Preferably, a 5-10% excess of the compoundrepresented by Structural Formula XIV is used. The reaction is typicallyperformed at concentrations of between about 0.01 M to about 5.0 M ofthe, preferably from about 0.1 M to about 1.0 M at temperatures rangingfrom about 0° C. to about 70° C., preferably at about room temperature.Specific conditions for performing the reaction are provided in theExample.

[0062] Oxazolidines included in Structural Formula XI can be used as areagent in the Ugi reaction to prepare new combinatorial libraries fordrug discovery. For oxazolines included in Structural Formula XI, theamine represented by R₄₂ can be deprotected by standard means. Theresulting compound has a free amine which can react in the Ugi reaction.

[0063] An “amino acid” is compound represented by NH₂—CHR—COOH, whereinR is —H, an aliphatic group, a substituted aliphatic group, an aromaticgroup or a substituted aromatic group. A “naturally-occurring aminoacid” is found in nature. Examples include alanine, valine, leucine,isoleucine, aspartic acid, glutamic acid, serine, threonine, glutamine,asparagine, arginine, lysine, omithine, proline, hydroxyproline,phenylalanine, tyrosine, tryptophan, cysteine, methionine and histidine.R is the side-chain of the amino acid. Examples of naturally occurringamino acid side-chains include methyl (alanine), isopropyl (valine),sec-butyl (isoleucine), —CH₂CH(—CH₃)₂ (leucine), benzyl (phenylalanine),p-hydroxybenzyl (tyrosine), —CH₂OH (serine), —CHOHCH₃ (threonine),—CH₂-3-indoyl (tryptophan), —CH₂COOH (aspartic acid), —CH₂CH₂COOH(glutamic acid), —CH₂C(O)NH₂ (asparagine), —CH₂CH₂C(O)NH₂ (glutamine),—CH_(S)SH, (cysteine), —CH₂CH₂SCH₃ (methionine), —(CH₂)₄NH₂ (lysine),—(CH₂)₃NH₂ (ornithine), —[(CH)₂]₄NHC(═NH)NH₂ (arginine) and—CH₂-3-imidazoyl (histidine).

[0064] The side-chains of alanine, valine, leucine and isoleucine arealiphatic, i.e., contain only carbon and hydrogen, and are each referredto herein as “the aliphatic side-chain of a naturally occurring aminoacid.”

[0065] The side-chains of other naturally-occurring amino acids comprisea heteroatom-containing functional group, e.g., an alcohol (serine,tyrosine, hydroxyproline and threonine), an amine (lysine, omithine,histidine and arginine), a thiol (cysteine) or a carboxylic acid(aspartic acid and glutamic acid). When the heteroatom-containingfunctional group is modified to include a protecting group, theside-chain is referred to as the “protected side-chain” of an aminoacid.

[0066] The selection of a suitable protecting group depends upon thefunctional group being protected, the conditions to which the protectinggroup is being exposed and to other functional groups which may bepresent in the molecule. Suitable protecting groups for the functionalgroups discussed above are described in Greene and Wuts, “ProtectiveGroups in Organic Synthesis”, John Wiley & Sons (1991), the entireteachings of which are incorporated into this application by reference.The skilled artisan can select, using no more than routineexperimentation, suitable protecting groups for use in the disclosedsynthesis, including protecting groups other than those described below,as well as conditions for applying and removing the protecting groups.

[0067] Examples of suitable alcohol protecting groups include benzyl,allyl, trimethylsilyl, tert-butyldimethylsilyl, acetate, and the like.Benzyl is a preferred alcohol protecting group.

[0068] Examples of suitable amino protecting groups includebenzyloxycarbonyl, tert-butoxycarbonyl, tert-butyl, benzyl andfluorenylmethyloxycarbonyl (Fmoc). Tert-butoxycarbonyl is a preferredamine protecting group.

[0069] Examples of suitable carboxylic acid protecting groups includetert-butyl, Fmoc, methyl, methoxylmethyl, trimethylsilyl,benzyloxymethyl, tert-butyldimethylsilyl and the like. Tert-butyl is apreferred carboxylic acid protecting group.

[0070] Examples of suitable thiol protecting groups include S-benzyl,S-tert-butyl, S-acetyl, S-methoxymethyl and the like.

[0071] Lysine, aspartate and threonine are examples of amino acidside-chains that are preferably protected. The following structures areexamples of a protected lysine side-chain, a protected aspartateside-chain and a protected threonine side-chain, respectively:

[0072] Aliphatic groups include straight chained, branched C₁-C₈, orcyclic C₃-C₈ hydrocarbons which are completely saturated or whichcontain one or more units of unsaturation. In one example, an aliphaticgroup is a C1-C4 alkyl group.

[0073] Aromatic groups include carbocyclic aromatic groups such asphenyl, 1-naphthyl, 2-naphthyl, 1-anthracyl and 2-anthracyl, andheterocyclic aromatic groups such as N-imidazolyl, 2-imidazole,2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-pyrimidy, 4-pyrimidyl, 2-pyranyl, 3-pyranyl, 3-pyrazolyl,4-pyrazolyl, 5-pyrazolyl, 2-pyrazinyl, 2-thiazole, 4-thiazole,5-thiazole, 2-oxazolyl, 4-oxazolyl and 5-oxazolyl.

[0074] Aromatic groups also include fused polycyclic aromatic ringsystems in which a carbocyclic aromatic ring or heteroaryl ring is fusedto one or more other heteroaryl rings. Examples include 2-benzothienyl,3-benzothienyl, 2-benzofuranyl, 3-benzofuranyl, 2-indolyl, 3-indolyl,2-quinolinyl, 3-quinolinyl, 2-benzothiazole, 2-benzooxazole,2-benzimidazole, 2-quinolinyl, 3-quinolinyl, 1-isoquinolinyl,3-quinolinyl, 1-isoindolyl, 3-isoindolyl, and acridintyl.

[0075] Preferred aromatic groups include the following groups:

[0076] Suitable substituents for an aryl group and aliphatic group arethose which are compatible with the disclosed reactions, i.e., do notsignificantly reduce the yield of the reactions and do not cause asignificant amount of side reactions. Suitable substituents generallyinclude aliphatic groups, substituted aliphatic groups, aryl groups,halogens, halogenated alkyl groups (e.g., trihalomethyl), nitro,nitrile, —CONHR, —CON(R)₂, —OR, —SR, —S(O)R, —S(O)₂R, wherein each R isindependently an aliphatic group, or an aryl group. Although certainfunctional groups may not be compatible with one or more of thedisclosed reactions, these functional groups may be present in aprotected form. The protecting group can then be removed to regeneratethe original functional group. The skilled artisan will be able toselect, using no more than routine experimentation, protecting groupswhich are compatible with the disclosed reactions.

[0077] Also included in the present invention are physiologicallyacceptable salts of the compounds represented by Structural Formulas I,II, V, VII, IX and XI. Salts of compounds containing an amine or otherbasic group can be obtained, for example, by reacting with a suitableorganic or inorganic acid, such as hydrogen chloride, hydrogen bromide,acetic acid, perchloric acid and the like. Compounds with a quaternaryammonium group also contain a counteranion such as chloride, bromide,iodide, acetate, perchlorate and the like. Salts of compounds containinga carboxylic acid or other acidic functional group can be prepared byreacting with a suitable base, for example, a hydroxide base. Salts ofacidic functional groups contain a countercation such as sodium,potassium and the like.

[0078] In the structural formulas depicted herein, the single or doublebond by which a chemical group or moiety is connected to the remainderof the molecule or compound is indicated by the following symbol:

[0079] For example, the corresponding symbol in Structural Formula XIIindicates that the nitrogen-bonded methine carbon in the pyrollidinering, is connected to the oxizolidine ring in Structural Formula XI by asingle covalent bond.

[0080] An Ugi Reaction can be performed by mixing an amine, a carboxylicacid, an isonitrile and an aldehyde or ketone in a suitable solvent suchas acetonitrile, methanol or dimethylsulfoxide at a concentration ofabout 250 mM for each reagent. Approximately equimolar amounts of eachreagent are generally used. The reaction is typically carried out attemperatures between about 20° C. and about 60° C., and preferably atroom temperature.

[0081] The invention is illustrated by the following example which arenot intended to be limiting in any way.

EXEMPLIFICATION EXAMPLE

[0082] Preparation of an Oxazolidine Represented by Structural FormulaXXVIII.

XXVIII Chemical name, purity Amount mmoles1-Amino-3-(S)-tert-butylcarbamido- 140.0 mg 0.52-(R)-hydroxy-4-phenylbutane Trimethylacetaldehyde, 97% 60 μl 0.55Acetonitrile, anhydrous, 99% 30 ml —

[0083] Procedure:

[0084] Trimethylacetaldehyde was added to a suspension of1-amino-3-(S)-tert-butylcarbamido-2-(R)-hydroxy-4-phenylbutane inanhydrous acetonitrile (2 mL). The mixture became thinner as some of thesolid went into solution, but after awhile became thick as a newsolid-started to form. More acetonitrile (1 mL) was added to facilitatestirring. After 5 h, a sample was withdrawn and dried under high vacuum.¹H NMR analysis indicated that oxazolidine formation had proceeded to anappreciable extent. The reaction was allowed to stir at room temperatureovernight.

[0085] The white precipitate was collected by suction filtration, washedwith a small amount of anhydrous acetonitrile (˜1 mL) and dried underhigh vacuum. The filtrate was concentrated to dryness to give a whitesolid which was dried under high vacuum. The combined yield was 164.3 mg(94.4%). This solid could be used without any further manipulation.

[0086] Equivalents

[0087] While this invention has been particularly shown and describedwith references to preferred embodiments thereof, it will be understoodby those skilled in the art that various changes in form and details maybe made therein without departing from the scope of the inventionencompassed by the appended claims.

What is claimed is:
 1. A method of preparing an imidazole represented bythe following structural formula:

or salts thereof, wherein: R₂₁ and R₂₂ are each, independently, —H, analiphatic group, a substituted aliphatic group, an aromatic group or asubstituted aromatic group, comprising the step of reacting an aliphaticcarboxylic acid and an ammonium salt of the aliphatic carboxylic acidwith a compound represented by the following structural formula:

thereby forming said imidazole.
 2. The method of claim 1, wherein: R₂₁is a C1-C4 alkyl; and R₂₂ is an aliphatic side-chain of a naturallyoccurring amino acid.
 3. A compound represented by the followingstructural formula:

or salts thereof, wherein: R₂₁ and R₂₂ are each, independently, —H, analiphatic group, a substituted aliphatic group, an aromatic group or asubstituted aromatic group.